The recent discoveries of KI, WU, and Merkel cell polyomaviruses (PyVs) have rekindled interest in the Polyomaviridae and their relation to human disease. Although it may be too early to draw firm conclusions, it seems apparent that these new viruses follow precedents established by other Py viruses: a benign initial infection at an early age, widespread prevalence in the population, and pathologic consequences only in the elderly and/or immunosuppressed. The discovery of Merkel cell PyV (MCPyV) integration into the malignant cell genome immediately implicates this agent in an oncogenic process predicted by previous research with SV40 and murine PyV (MPyV). Their discovery is another reminder that we certainly have not seen the end of novel human polyomavirus identification, but rather the beginning of a new era.